Dopamine is a neurotransmitter in the central nervous system that has been implicated in the etiology and treatment of several neurological and psychiatric disorders, such as schizophrenia, narcolepsy, restless leg syndrome, and Parkinson's disease, and of other disorders such as shock, including septic shock, congestive heart failure, arrhythmias, hypotension, and hypertension. Exemplary of these disorders, Parkinson's disease is a neurological disorder characterized by an inability to control the voluntary motor system. Parkinson's disease involves the progressive degeneration of dopaminergic neurons, and, thus, Parkinson's disease results from insufficient dopaminergic activity. The principal approach in pharmacotherapy of Parkinson's disease has been dopamine replacement therapy using L-DOPA (L-dihydroxyphenylalanine or levodopa), a drug that can provide significant palliative effects for several years. The principal limitations of the long-term use of L-DOPA, however, include the development of unpredictable “on-off” phenomena, dyskinesias, psychiatric symptoms such as hallucinations, and eventual loss of efficacy.
To avoid these adverse events, direct-acting dopamine receptor agonists targeted for specific classes of dopamine receptors have been tried. Dopamine receptors have traditionally been classified into two families (the D1 and D2 dopamine receptor families) based on pharmacological and functional evidence. D1 receptors generally lead to stimulation of the enzyme adenylate cyclase, whereas D2 receptors often are coupled negatively (or not at all) to adenylate cyclase. Dopamine receptors are further classified by their agonist (receptor activating) or antagonist (receptor blocking) activity.
D2-preferring agonists, such as bromocriptine, ropinirole, and pramipexole, have been found to be useful in the early stages of Parkinson's disease, losing efficacy as the illness progresses. Efforts to develop D1 agonists for the treatment of Parkinson's disease have met with limited success. For example, SKF-38393 and CY 208-243 were efficacious in rodent models, but were less effective in parkinsonian primates or humans. These compounds are partial agonists at D1 receptors suggesting the need for full intrinsic activity at the D1 receptor. The differentiation between D1 agonists of full and partial efficacy is important because this may influence the actions of dopamine receptor agonists on complex central nervous system mediated events.
This hypothesis is supported by recent studies showing that several D1 receptor full agonists are efficacious in non-human primate Parkinson's disease models and in humans with Parkinson's disease. Accordingly, researchers have directed their efforts to design ligands that are full agonists (i.e., have full intrinsic efficacy) for the D1 receptor. One such compound is dihydrexidine, a hexahydrobenzo[a]phenanthridine of the formula: The structure of dihydrexidine is unique from other D1 agonists because the accessory ring system is tethered, making the molecule relatively rigid. The dihydrexidine-based model has served as the basis for the design of additional D1 receptor agonists. The design and synthesis of D1 receptor agonists having high intrinsic activity is important to the medical research community due to the potential use of full agonists to treat complex central nervous system mediated events, and also conditions in which peripheral dopamine receptors are involved.
Among the D1 receptor agonists with full intrinsic activity developed based on the dihydrexidine model is a novel class of dopamine receptor agonists of the general formula: Two such compounds are dinoxyline and dinapsoline, fused isoquinolines of the formulas: Dihydrexidine, dinoxyline, and dinapsoline function as full agonists of D1 receptors. However, many full agonists have not evolved for clinical use either due to pharmacokinetic limitations or rapid development of tolerance (i.e., loss of therapeutic effects despite administration of the same or larger doses of drug). Therefore, requirements for D1 agonists for Parkinson's disease therapy and for treatment of other neurological disorders and conditions involving peripheral dopamine receptors, include full intrinsic efficacy at D1 receptors and failure to induce tolerance.
The present invention provides a method of treating disorders resulting from dopamine-related dysfunction, such as Parkinson's disease, by using a full D1 dopamine receptor agonist in an intermittent dosing protocol. According to this protocol, the plasma concentration of the D1 agonist is reduced to a concentration below the level required for optimal dopamine receptor stimulation (e.g., the concentration of the D1 agonist at the D1 receptor can be decreased to a level such that receptor occupation is negligible (<5% high affinity)) for a time sufficient (i.e., at least one hour per each 24 hour period) to prevent the induction of tolerance. This dosing protocol is useful for treating patients having a dopamine-related dysfunction of the central nervous system (as evidenced by an apparent neurological, psychological, physiological, or behavioral disorder), as well as conditions in which peripheral dopamine receptors are involved (including target tissues such as the kidney, lung, endocrine, and cardiovascular systems).
In one embodiment of the invention, a method of treating a disorder resulting from dopamine-related dysfunction is provided. The method comprises the steps of administering to a patient a full D1 agonist wherein said agonist has a half-life of less than 6 hours and wherein said agonist is administered at a dose resulting in a first plasma concentration of agonist capable of activating D1 dopamine receptors to produce a therapeutic effect, and reducing said agonist dose at least once every 24 hours to obtain a second lower plasma concentration of agonist wherein said second concentration of agonist results in suboptimal activation of D1 dopamine receptors for a period of time sufficient to prevent induction of tolerance.
In another embodiment of the invention the agonist is selected from the group consisting of dinapsoline, dinoxyline, dihydrexidine, other D1 agonists, analogs and derivatives of these agonists, and combinations thereof.
In yet another embodiment of the invention, the disorder is selected from the group consisting of Parkinson's disease, autism, attention deficit disorder, schizophrenia, restless leg syndrome, memory loss, and sexual dysfunction.